tbuckley/cabot-search huggingface dataset:
Tumor and immune cell types interact to produce heterogeneous phenotypes of pediatric high-grade glioma
Authors: John DeSisto, Andrew M Donson, Andrea M Griesinger, Rui Fu, Kent Riemondy, Jean Mulcahy Levy, Julie A Siegenthaler, Nicholas K Foreman, Rajeev Vibhakar, Adam L Green
Journal: Neuro-Oncology (2023)

Abstract Background Pediatric high-grade gliomas (PHGG) are aggressive brain tumors with 5-year survival rates ranging from &amp;lt;2% to 20% depending upon subtype. PHGG presents differently from patient to patient and is intratumorally heterogeneous, posing challenges in designing therapies. We hypothesized that heterogeneity occurs because PHGG comprises multiple distinct tumor and immune cell types in varying proportions, each of which may influence tumor characteristics. Methods We obtained 19 PHGG samples from our institution’s pediatric brain tumor bank. We constructed a comprehensive transcriptomic dataset at the single-cell level using single-cell RNA-Seq (scRNA-Seq), identified known glial and immune cell types, and performed differential gene expression and gene set enrichment analysis. We conducted multi-channel immunofluorescence (IF) staining to confirm the transcriptomic results. Results Our PHGG samples included 3 principal predicted tumor cell types: astrocytes, oligodendrocyte progenitors (OPCs), and mesenchymal-like cells (Mes). These cell types differed in their gene expression profiles, pathway enrichment, and mesenchymal character. We identified a macrophage population enriched in mesenchymal and inflammatory gene expression as a possible source of mesenchymal tumor characteristics. We found evidence of T-cell exhaustion and suppression. Conclusions PHGG comprises multiple distinct proliferating tumor cell types. Microglia-derived macrophages may drive mesenchymal gene expression in PHGG. The predicted Mes tumor cell population likely derives from OPCs. The variable tumor cell populations rely on different oncogenic pathways and are thus likely to vary in their responses to therapy.
RE: Use of artificial intelligence for cancer clinical trial enrollment
Authors: Jiawen Deng, Kiyan Heybati
Journal: JNCI Journal of the National Cancer Institute (2023)

Clinical trials represent a pivotal step in advancing novel cancer therapies from development to clinical application.Despite a strong willingness among patients to participate, however, less than 5% of adult patients with cancer are enrolled in oncology trials.Enhancing enrollment workflows can expedite treatment advances and lead to faster patient outcome improvements (1).In their review in this issue of the Journal, Chow et al. ( 2) found that artificial intelligence (AI) workflows for trial enrollment outperformed manual methods, with industry-developed systems having higher positive predictive values than in-house systems.Although we commend Chow et al. for their comprehensive review, we believe that certain concerns warrant further discussion.First, the AI workflows examined had substantial heterogeneities, which complicates the meta-analysis and interpretation of AI performance.AI enrollment workflows can generally be broken down into 3 steps: 1) extracting eligibility criteria from protocols, 2) extracting data from electronic health records, and 3) matching the extracted data with the eligibility criteria (3).The studies included in the review differed greatly in how they approached these steps.For instance, where Meystre et al. (3) applied AI only to the latter 2 steps, Beck et al. (4) automated all 3. Thus, the accuracy of Meystre et al.'s workflow would be less affected by AI than that of Beck et al.Meanwhile, other studies, such as Calaprice-Whitty et al. ( 5), incorporated auxiliary systems such as optical character recognition, which introduced additional failure points that could reduce the study's accuracy.
Lipid nanoparticles for targeted delivery of anticancer therapeutics: Recent advances in development of siRNA and lipoprotein-mimicking nanocarriers
Authors: Anan Yaghmur, Jesper Østergaard, Huiling Mu
Journal: Advanced Drug Delivery Reviews (2023)

The limitations inherent in conventional cancer treatment methods have stimulated recent efforts towards the design of safe nanomedicines with high efficacy for combating cancer through various promising approaches. A plethora of nanoparticles has been introduced in the development of cancer nanomedicines. Among them, different lipid nanoparticles are attractive for use due to numerous advantages and unique opportunities, including biocompatibility and targeted drug delivery. However, a comprehensive understanding of nano-bio interactions is imperative to facilitate the translation of recent advancements in the development of cancer nanomedicines into clinical practice. In this contribution, we focus on lipoprotein-mimicking nanoparticles, which possess unique features and compositions facilitating drug transport through receptor binding mechanisms. Additionally, we describe potential applications of siRNA lipid nanoparticles in the future design of anticancer nanomedicines. Thus, this review highlights recent progress, challenges, and opportunities of lipid-based lipoprotein-mimicking nanoparticles and siRNA nanocarriers designed for the targeted delivery of anticancer therapeutic agents.
ETV4-Dependent Transcriptional Plasticity Maintains <i>MYC</i> Expression and Results in IMiD Resistance in Multiple Myeloma
Authors: Paola Neri, Benjamin G. Barwick, David Jung, Jonathan C. Patton, Ranjan Maity, Ines Tagoug, Caleb K. Stein, Remi Tilmont, Noemie Leblay, Sungwoo Ahn, Holly Lee, Seth J. Welsh, Daniel L. Riggs, Nicholas Stong, Erin Flynt, Anjan Thakurta, Jonathan J. Keats, Sagar Lonial, P. Leif Bergsagel, Lawrence H. Boise, Nizar J. Bahlis
Journal: Blood Cancer Discovery (2023)

Abstract Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance. Significance: We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4
Contractility measurements for cardiotoxicity screening with ventricular myocardial slices of pigs
Authors: Runzhu Shi, Marius Reichardt, Dominik J Fiegle, Linda K Küpfer, Titus Czajka, Zhengwu Sun, Tim Salditt, Andreas Dendorfer, Thomas Seidel, Tobias Bruegmann
Journal: Cardiovascular Research (2023)

Abstract Aims Cardiotoxicity is one major reason why drugs do not enter or are withdrawn from the market. Thus, approaches are required to predict cardiotoxicity with high specificity and sensitivity. Ideally, such methods should be performed within intact cardiac tissue with high relevance for humans and detect acute and chronic side effects on electrophysiological behaviour, contractility, and tissue structure in an unbiased manner. Herein, we evaluate healthy pig myocardial slices and biomimetic cultivation setups (BMCS) as a new cardiotoxicity screening approach. Methods and results Pig left ventricular samples were cut into slices and spanned into BMCS with continuous electrical pacing and online force recording. Automated stimulation protocols were established to determine the force–frequency relationship (FFR), frequency dependence of contraction duration, effective refractory period (ERP), and pacing threshold. Slices generated 1.3 ± 0.14 mN/mm2 force at 0.5 Hz electrical pacing and showed a positive FFR and a shortening of contraction duration with increasing pacing rates. Approximately 62% of slices were able to contract for at least 6 days while showing stable ERP, contraction duration–frequency relationship, and preserved cardiac structure confirmed by confocal imaging and X-ray diffraction analysis. We used specific blockers of the most important cardiac ion channels to determine which analysis parameters are influenced. To validate our approach, we tested five drug candidates selected from the Comprehensive in vitro Proarrhythmia Assay list as well as acetylsalicylic acid and DMSO as controls in a blinded manner in three independent laboratories. We were able to detect all arrhythmic drugs and their respective mode of action on cardiac tissue including inhibition of Na+, Ca2+, and hERG channels as well as Na+/Ca2+ exchanger. Conclusion We systematically evaluate this approach for cardiotoxicity screening, which is of high relevance for humans and can be upscaled to medium-throughput screening. Thus, our approach will improve the predictive value and efficiency of preclinical cardiotoxicity screening.
Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma
Authors: Selene Clay, Jehan Alladina, Neal P. Smith, Cynthia M. Visness, Robert A. Wood, George T. O’Connor, Robyn T. Cohen, Gurjit K. Khurana Hershey, Carolyn M. Kercsmar, Rebecca S. Gruchalla, Michelle A. Gill, Andrew H. Liu, Haejin Kim, Meyer Kattan, Leonard B. Bacharier, Deepa Rastogi, Katherine Rivera-Spoljaric, Rachel G. Robison, Peter J. Gergen, William W. Busse, Alexandra-Chloe Villani, Josalyn L. Cho, Benjamin D. Medoff, James E. Gern, Daniel J. Jackson, Carole Ober, Matthew Dapas
Journal: Journal of Allergy and Clinical Immunology (2023)

Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits.
Diabetes Mellitus, Energy Metabolism, and COVID-19
Authors: Caterina Conte, Elisa Cipponeri, Michael Roden
Journal: Endocrine Reviews (2023)

Abstract Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.
Optical coherence tomography in the management of diabetic macular oedema
Authors: Simon KH. Szeto, Timothy YY. Lai, Stela Vujosevic, Jennifer K. Sun, SriniVas R. Sadda, Gavin Tan, Sobha Sivaprasad, Tien Y. Wong, Carol Y. Cheung
Journal: Progress in Retinal and Eye Research (2023)
The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease
Authors: Keisuke Sawada, Hak Chung, Samir Softic, Maria E. Moreno-Fernandez, Senad Divanovic
Journal: Cell Metabolism (2023)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.
Unusual Case of Primary Hepatic Squamous Carcinoma on 18F-FDG PET/CT
Authors: Wei Li, Zhidong Liu, Rusen Zhang
Journal: Clinical Nuclear Medicine (2023)

Primary hepatic squamous carcinoma is an extremely rare liver tumor type with high malignancy and poor prognosis. We present 18F-FDG PET/CT findings of primary squamous carcinoma of the liver in a 65-year-old man, who was admitted to the hospital with subxiphoid pain in the epigastric region radiating to the left lower back for 2 months. 18F-FDG PET/CT demonstrated a large heterogeneous mild enhancing mass in the left lobe of the liver, with intense circumferential 18F-FDG activity.
Quantifying the impact of AI recommendations with explanations on prescription decision making
Authors: Myura Nagendran, Paul Festor, Matthieu Komorowski, Anthony C. Gordon, Aldo A. Faisal
Journal: npj Digital Medicine (2023)

Abstract The influence of AI recommendations on physician behaviour remains poorly characterised. We assess how clinicians’ decisions may be influenced by additional information more broadly, and how this influence can be modified by either the source of the information (human peers or AI) and the presence or absence of an AI explanation (XAI, here using simple feature importance). We used a modified between-subjects design where intensive care doctors ( N = 86) were presented on a computer for each of 16 trials with a patient case and prompted to prescribe continuous values for two drugs. We used a multi-factorial experimental design with four arms, where each clinician experienced all four arms on different subsets of our 24 patients. The four arms were (i) baseline (control), (ii) peer human clinician scenario showing what doses had been prescribed by other doctors, (iii) AI suggestion and (iv) XAI suggestion. We found that additional information (peer, AI or XAI) had a strong influence on prescriptions (significantly for AI, not so for peers) but simple XAI did not have higher influence than AI alone. There was no correlation between attitudes to AI or clinical experience on the AI-supported decisions and nor was there correlation between what doctors self-reported about how useful they found the XAI and whether the XAI actually influenced their prescriptions. Our findings suggest that the marginal impact of simple XAI was low in this setting and we also cast doubt on the utility of self-reports as a valid metric for assessing XAI in clinical experts.
Large Bladder Stone Detected on Renal Scintigraphy
Authors: Yan Deng, Juan Su, Zhaohui Liu, Wei Zhang, Xiaoping Lei
Journal: Clinical Nuclear Medicine (2023)

A 39-year-old woman with hydronephrosis underwent 99mTc-DTPA renal dynamic scintigraphy to evaluate renal function. The images revealed a central photopenic region in the urinary bladder. SPECT/CT images suggested the abnormal tracer distribution corresponding to a large urinary bladder stone.
Solitary Neuroblastoma in the Scapula
Authors: Raisa Amiruddin, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2023)

Majority of primary pediatric neuroblastomas occur in the abdomen, followed by posterior mediastinum. A 7-year-old girl presented worsening pain in the left shoulder, and a CT image of the chest revealed osseous destruction in the left scapula, suggestive of bone tumor. A biopsy was performed. Pathological result was consistent with neuroblastoma. A 123I scan with SPECT/CT images was performed, which showed only increased activity in the left scapula without any other foci of abnormal activity elsewhere.
Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma
Authors: Manon de Vries-Brilland, Nathalie Rioux-Leclercq, Maxime Meylan, Jonathan Dauvé, Christophe Passot, Elena Spirina-Menand, Ronan Flippot, Gaëlle Fromont, Gwenaelle Gravis, Lionnel Geoffrois, Christine Chevreau, Fréderic Rolland, Ellen Blanc, Félix Lefort, Alain Ravaud, Marine Gross-Goupil, Bernard Escudier, Sylvie Negrier, Laurence Albiges
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets. Methods We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort. Results Unsupervised clustering identified two “TME subtypes”, in each of the cohorts: the “immune-enriched” and the “immune-low”. Within AXIPAP trial cohort, the “immune-enriched” cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the “immune-enriched” group (adjusted p&lt;0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations. Conclusion For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This “immune-enriched” group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies. Trial registration number NCT02489695 .
Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy
Authors: Selena Ferrian, Aiqin Cao, Erin F. McCaffrey, Toshie Saito, Noah F. Greenwald, Mark R. Nicolls, Trevor Bruce, Roham T. Zamanian, Patricia Del Rosario, Marlene Rabinovitch, Michael Angelo
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Unraveling immune-driven vascular pathology in pulmonary arterial hypertension (PAH) requires a comprehensive understanding of the immune cell landscape. Although patients with hereditary (H)PAH and bone morphogenetic protein receptor type 2 (BMPR2) mutations have more severe pulmonary vascular pathology, it is not known whether this is related to specific immune cell subsets.
Spatial Transcriptomics Resolve an Emphysema-Specific Lymphoid Follicle B Cell Signature in Chronic Obstructive Pulmonary Disease
Authors: Joselyn Rojas-Quintero, Scott A. Ochsner, Felicia New, Prajan Divakar, Chen Xi Yang, Tianshi David Wu, Jerid Robinson, Darshan Shimoga Chandrashekar, Nicholas E. Banovich, Ivan O. Rosas, Maor Sauler, Farrah Kheradmand, Amit Gaggar, Camilla Margaroli, Raul San Jose Estepar, Neil J. McKenna, Francesca Polverino
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component.
Screening, Referral, Behavioral Counseling, and Preventive Interventions for Oral Health in Adults
Authors: Roger Chou, Shelley S. Selph, Christina Bougatsos, Chad Nix, Azrah Ahmed, Jessica Griffin, Eli Schwarz
Journal: JAMA (2023)

Dental caries and periodontal disease are common adult oral health conditions and potentially amenable to primary care screening and prevention.To systematically review the evidence on primary care screening and prevention of dental caries and periodontal disease in adults to inform the US Preventive Services Task Force.MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to October 3, 2022); surveillance through July 21, 2023.Diagnostic accuracy studies of primary care screening instruments and oral examination; randomized and nonrandomized trials of screening and preventive interventions; cohort studies on primary care oral health screening and preventive intervention harms.One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Diagnostic accuracy data were pooled using a bivariate mixed-effects binary regression model.Dental caries, periodontal disease, morbidity, quality of life, harms; and diagnostic test accuracy.Five randomized clinical trials, 5 nonrandomized trials, and 6 observational studies (total 3300 participants) were included. One poor-quality trial (n = 477) found no difference between oral health screening during pregnancy vs no screening in caries, periodontal disease, or birth outcomes. One study (n = 86) found oral health examination by 2 primary care clinicians associated with low sensitivity (0.42 and 0.56) and high specificity (0.84 and 0.87) for periodontal disease and with variable sensitivity (0.33 and 0.83) and high specificity (0.80 and 0.93) for dental caries. Four studies (n = 965) found screening questionnaires associated with a pooled sensitivity of 0.72 (95% CI, 0.57-0.83) and specificity of 0.74 (95% CI, 0.66-0.82) for periodontal disease. For preventive interventions no study evaluated primary care counseling or dental referral, and evidence from 2 poor-quality trials (n = 178) of sealants, and 1 fair-quality and 4 poor-quality trials (n = 971) of topical fluorides, was insufficient. Three fair-quality trials (n = 590) of persons with mean age 72 to 80 years found silver diamine fluoride solution associated with fewer new root caries lesions or fillings vs placebo (mean reduction, -0.33 to -1.3) and decreased likelihood of new root caries lesion (2 trials; adjusted odds ratio, 0.4 [95% CI, 0.3-0.7]). No trial evaluated primary care-administered preventive interventions.Screening questionnaires were associated with moderate diagnostic accuracy for periodontal disease. Research is needed to determine benefits and harms of oral health primary care screening and preventive interventions.